Particles in Parenteralia - FDA’s perspective

In the course of this year’s ECA conference "Particles in Parenterals" Dr Stephen E. Langille, CDER, FDA talked about the problems concerning particulate matter in injectable drug products from the point of view of the US-American FDA. At the beginning of his lecture he cited Janet Woodcock: “The FDA considers high-quality drug products to be those that consistently and reliably deliver the clinical performance and other characteristics stated in the label, are not contaminated, and are available.”

Naturally, this statement is of great importance regarding particulate matter in parenterals. Due to production-related issues a specification of 0 particles is not possible. But according to Dr Langille precisely this requirement is not really clear enough in the different pharmacopoeias USP, PhEur and JP. According to him, it must be ensured by means of the 100% visual inspection that a batch is essentially free from visible particles. Each container of a batch must be definitely free from particles or it must be rejected in the course of the visual inspection. Then, Dr Langille further elaborated on the concerns of the FDA regarding particulate matter. Even if there are only few cases of patients documented that were harmed or even died due to particulate matter, the FDA considers particles in drug products for parenteral use as posing a risk. Dr Langille emphasized that the estimated number of unknown cases might be considerably higher. Patients with chronic lung diseases, for example, might suffer or die due to emboli caused by eventually undetected particles. The physical complaints of these patients or their death would be attributed to their primary disease and not to the infusion contaminated by particles.

Stephen Langille explained that the FDA has a risk-based way of considering reports on batches of drug products on the market in which particles were found. The following risk factors are taken into consideration: the route of administration, the composition of the particles, the group of patients taking the drug product, the number of particles and their size. The FDA considers that the risk is less in the case of subcutaneous or intravitreous administration than in the case of intravenous administration. As concerns the composition silicone particles, drug substance precipitates or skin cells are considered to be less critical than for instance glass, stainless steel or rust particles. For the body it is considerably more difficult to get rid of this sort of particles. According to the FDA children and newborns, especially premature babies that have to be fed parenterally are the patient group with the highest risk. This group is followed by older patients and the chronically sick. As concerns the number of particles, obviously the dose or amount of drug product to be taken is crucial. LVP (Large Volume Parenterals) pose the highest risk, followed by solutions for infusions and then by dosage forms administered only once such as vaccinations. In this context Dr Langille addressed the ampoule that in his words is “still” used as container for parenterals. According to him this is absolutely incomprehensible since the generation of particles is inherent to the system in the case of ampoules. Especially, if patients open the ampoule, particles are generated in a totally uncontrolled way.